tbuckley/cabot-search huggingface dataset:
Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3′ untranslated region
Authors: Lara P. Fernández, Nerea Deleyto-Seldas, Gonzalo Colmenarejo, Alba Sanz, Sonia Wagner, Ana Belén Plata-Gómez, Mónica Gómez-Patiño, Susana Molina, Isabel Espinosa-Salinas, Elena Aguilar-Aguilar, Sagrario Ortega, Osvaldo Graña-Castro, Viviana Loria-Kohen, Pablo J. Fernández-Marcos, Alejo Efeyan, Ana Ramírez de Molina
Journal: Genome biology (2022)

Abstract Background Overweight and obesity are defined by an anomalous or excessive fat accumulation that may compromise health. To find single-nucleotide polymorphisms (SNPs) influencing metabolic phenotypes associated with the obesity state, we analyze multiple anthropometric and clinical parameters in a cohort of 790 healthy volunteers and study potential associations with 48 manually curated SNPs, in metabolic genes functionally associated with the mechanistic target of rapamycin (mTOR) pathway. Results We identify and validate rs2291007 within a conserved region in the 3′UTR of folliculin-interacting protein FNIP2 that correlates with multiple leanness parameters. The T-to-C variant represents the major allele in Europeans and disrupts an ancestral target sequence of the miRNA miR-181b-5p, thus resulting in increased FNIP2 mRNA levels in cancer cell lines and in peripheral blood from carriers of the C allele. Because the miRNA binding site is conserved across vertebrates, we engineered the T-to-C substitution in the endogenous Fnip2 allele in mice. Primary cells derived from Fnip2 C/C mice show increased mRNA stability, and more importantly, Fnip2 C/C mice replicate the decreased adiposity and increased leanness observed in human volunteers. Finally, expression levels of FNIP2 in both human samples and mice negatively associate with leanness parameters, and moreover, are the most important contributor in a multifactorial model of body mass index prediction. Conclusions We propose that rs2291007 influences human leanness through an evolutionarily conserved modulation of FNIP2 mRNA levels. Graphical Abstract
Low Baseline CXCL9 Predicts Early Progressive Disease in Unresectable HCC with Atezolizumab Plus Bevacizumab Treatment
Authors: Shunichi Hosoda, Goki Suda, Takuya Sho, Koji Ogawa, Megumi Kimura, Zijian Yang, Sonoe Yoshida, Akinori Kubo, Yoshimasa Tokuchi, Takashi Kitagataya, Osamu Maehara, Shunsuke Ohnishi, Akihisa Nakamura, Ren Yamada, Masatsugu Ohara, Naoki Kawagishi, Mitsuteru Natsuizaka, Masato Nakai, Kenichi Morikawa, Ken Furuya, Masaru Baba, Yoshiya Yamamoto, Kazuharu Suzuki, Takaaki Izumi, Takashi Meguro, Katsumi Terashita, Jun Ito, Takuto Miyagishima, Naoya Sakamoto
Journal: Liver Cancer (2022)

Atezolizumab plus bevacizumab treatment is highly effective in patients with unresectable hepatocellular carcinoma (HCC). However, progressive disease (PD) occurs in approximately 20% of HCC patients treated with atezolizumab plus bevacizumab, resulting in a poor prognosis. Thus, the prediction and early detection of HCC is crucial.Patients with unresectable HCC treated with atezolizumab plus bevacizumab and had baseline preserved serum (n = 68) were screened and classified according to their PD, 6 weeks after treatment initiation (early PD; n = 13). Of these, 4 patients each with and without early PD were selected for cytokine array and genetic analyses. The identified factors were validated in the validated cohort (n = 60) and evaluated in patients treated with lenvatinib.No significant differences were observed in the genetic alterations in circulating tumor DNA. Cytokine array data revealed that baseline MIG (CXCL9), ENA-78, and RANTES differed substantially between patients with and without early PD. Subsequent analysis in the validation cohort revealed that baseline CXCL9 was significantly lower in patients with early PD than that in patients without early PD, and the best cut-off value of serum CXCL9 to predict early PD was 333 pg/mL (sensitivity: 0.600, specificity: 0.923, AUC = 0.75). In patients with lower serum CXCL9 (<333 pg/mL), 35.3% (12/34) experienced early PD with atezolizumab plus bevacizumab, while progression-free survival (PFS) was significantly shorter relative to that in patients without (median PFS, 126 days vs. 227 days; HR: 2.41, 95% CI: 1.22-4.80, p = 0.0084). While patients with objective response to lenvatinib had significantly lower CXCL9 levels compared with those of patients without.Baseline low serum CXCL9 (<333 pg/mL) levels may predict early PD in patients with unresectable HCC treated with atezolizumab plus bevacizumab.
Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 Inhibitors and Reaffirmation of the Nutrient Deprivation Signaling/Autophagy Hypothesis
Authors: Milton Packer
Journal: Circulation (2022)

SGLT2 (sodium-glucose cotransporter 2) inhibitors produce a distinctive pattern of benefits on the evolution and progression of cardiomyopathy and nephropathy, which is characterized by a reduction in oxidative and endoplasmic reticulum stress, restoration of mitochondrial health and enhanced mitochondrial biogenesis, a decrease in proinflammatory and profibrotic pathways, and preservation of cellular and organ integrity and viability. A substantial body of evidence indicates that this characteristic pattern of responses can be explained by the action of SGLT2 inhibitors to promote cellular housekeeping by enhancing autophagic flux, an effect that may be related to the action of these drugs to produce simultaneous upregulation of nutrient deprivation signaling and downregulation of nutrient surplus signaling, as manifested by an increase in the expression and activity of AMPK (adenosine monophosphate-activated protein kinase), SIRT1 (sirtuin 1), SIRT3 (sirtuin 3), SIRT6 (sirtuin 6), and PGC1-α (peroxisome proliferator-activated receptor γ coactivator 1-α) and decreased activation of mTOR (mammalian target of rapamycin). The distinctive pattern of cardioprotective and renoprotective effects of SGLT2 inhibitors is abolished by specific inhibition or knockdown of autophagy, AMPK, and sirtuins. In the clinical setting, the pattern of differentially increased proteins identified in proteomics analyses of blood collected in randomized trials is consistent with these findings. Clinical studies have also shown that SGLT2 inhibitors promote gluconeogenesis, ketogenesis, and erythrocytosis and reduce uricemia, the hallmarks of nutrient deprivation signaling and the principal statistical mediators of the ability of SGLT2 inhibitors to reduce the risk of heart failure and serious renal events. The action of SGLT2 inhibitors to augment autophagic flux is seen in isolated cells and tissues that do not express SGLT2 and are not exposed to changes in environmental glucose or ketones and may be related to an ability of these drugs to bind directly to sirtuins or mTOR. Changes in renal or cardiovascular physiology or metabolism cannot explain the benefits of SGLT2 inhibitors either experimentally or clinically. The direct molecular effects of SGLT2 inhibitors in isolated cells are consistent with the concept that SGLT2 acts as a nutrient surplus sensor, and thus, its inhibition causes enhanced nutrient deprivation signaling and its attendant cytoprotective effects, which can be abolished by specific inhibition or knockdown of AMPK, sirtuins, and autophagic flux.
Stromal structure remodeling by B lymphocytes limits T cell activation in lymph nodes of Mycobacterium tuberculosis–infected mice
Authors: Lina Daniel, Nayan D Bhattacharyya, Claudio Counoupas, Yi Cai, Xinchun Chen, James A Triccas, Warwick J Britton, Carl G Feng
Journal: Journal of Clinical Investigation (2022)

An effective adaptive immune response depends on the organized architecture of secondary lymphoid organs, including the lymph nodes (LNs). While the cellular composition and microanatomy of LNs under steady state are well defined, the impact of chronic tissue inflammation on the structure and function of draining LNs is incompletely understood. Here we showed that Mycobacterium tuberculosis infection remodeled LN architecture by increasing the number and paracortical translocation of B cells. The formation of paracortical B lymphocyte and CD35+ follicular dendritic cell clusters dispersed CCL21-producing fibroblastic reticular cells and segregated pathogen-containing myeloid cells from antigen-specific CD4+ T cells. Depletion of B cells restored the chemokine and lymphoid structure and reduced bacterial burdens in LNs of the chronically infected mice. Importantly, this remodeling process impaired activation of naive CD4+ T cells in response to mycobacterial and unrelated antigens during chronic tuberculosis infection. Our studies reveal a mechanism in the regulation of LN microanatomy during inflammation and identify B cells as a critical element limiting the T cell response to persistent intracellular infection in LNs.
A randomized phase III intergroup study of perioperative fluorouracil (5-FU) in patients with resectable colon cancer
Authors: M. M. Kemeny, S. Eapen, R. P. Whitehead, R. Bleday, R. E. Smith, A. B. Benson
Journal: Journal of Clinical Oncology (2005)

3552 Background: Data from previous trials suggest that a weeklong continuous infusion of 5FU started 24 hours after colon resection may improve survival. Methods: Patients were randomized to a continuous infusion of 5FU at 600mg/m2/day for 7 days starting within 24 hours of the end of curative colon resection or to no peri-operative chemotherapy(POC) (Step 1). Patients who had metastatic disease at operation or who had Dukes A or B1 colon lesion were placed off study. Patients with Dukes B2 lesions received the POC, but no post operative chemotherapy. All patients with Dukes B3 and C lesions, whether they received the peri-operative treatment or not, were reentered for standard postoperative chemotherapy (Step 2), with 5FU and levamisole. In August of 1997 the adjuvant chemotherapy was changed to the Mayo Clinic regimen of 5FU and leucovorin. The protocol, activated in August 1993, accrued 858 patients out of the targeted 2000 patients to Step 1 and 604 were re-registered at Step 2. The study was closed in May 2000 due to insufficient accrual. Results: Of the total cases 7% were Dukes A, 14% Dukes B1 and 7% were Dukes D; all were not re-registered. For the patients randomized 35% were B2, 4% B3 and 33% Dukes C. The median follow-up time is 7.4 years. There were 4 deaths in the peri-operative period, 3 in the chemotherapy arm. The difference in overall and progression free survival between the no POC arm and POC arm among the Dukes’ B3 and C patients was not significant, p-value=0.37 and 0.72, respectively. The 5 year overall survival for these patients in the no POC arm is 65% and 68% in the POC arm (log rank p-value = 0.74). Similarly, no differences were seen in overall and progression-free survival between the two arms in the Dukes’ B2 patients, p-value=0.14 and 0.17, respectively. The 5 year overall survival for the Dukes’ B2 patients is 77% in the no POC arm and 86%in the POC arm(log rank p-value = 0.068). Conclusions: Fluorouracil can be safely given as a continuous infusion in the immediate postoperative period after a colon resection. There is a trend toward increased survival in the patients receiving POC, especially in the B2 patients, but since this trial did not achieve its accrual goal, the study did not reach significance. No significant financial relationships to disclose.
First-in-human phase I/II, open-label study of the anti-OX40 agonist INCAGN01949 in patients with advanced solid tumors
Authors: Elizabeth J Davis, Juan Martin-Liberal, Rebecca Kristeleit, Daniel C Cho, Sarah P Blagden, Dominik Berthold, Dana B Cardin, Maria Vieito, Rowan E Miller, Prashanth Hari Dass, Angela Orcurto, Kristen Spencer, John E Janik, Jason Clark, Thomas Condamine, Jennifer Pulini, Xuejun Chen, Janice M Mehnert
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background OX40 is a costimulatory receptor upregulated on antigen-activated T cells and constitutively expressed on regulatory T cells (Tregs). INCAGN01949, a fully human immunoglobulin G1κ anti-OX40 agonist monoclonal antibody, was designed to promote tumor-specific immunity by effector T-cell activation and Fcγ receptor-mediated Treg depletion. This first-in-human study was conducted to determine the safety, tolerability, and preliminary efficacy of INCAGN01949. Methods Phase I/II, open-label, non-randomized, dose-escalation and dose-expansion study conducted in patients with advanced or metastatic solid tumors. Patients received INCAGN01949 monotherapy (7–1400 mg) in 14-day cycles while deriving benefit. Safety measures, clinical activity, pharmacokinetics, and pharmacodynamic effects were assessed and summarized with descriptive statistics. Results Eighty-seven patients were enrolled; most common tumor types were colorectal (17.2%), ovarian (8.0%), and non-small cell lung (6.9%) cancers. Patients received a median three (range 1–9) prior therapies, including immunotherapy in 24 patients (27.6%). Maximum tolerated dose was not reached; one patient (1.1%) receiving 350 mg dose reported dose-limiting toxicity of grade 3 colitis. Treatment-related adverse events were reported in 45 patients (51.7%), with fatigue (16 (18.4%)), rash (6 (6.9%)), and diarrhea (6 (6.9%)) being most frequent. One patient (1.1%) with metastatic gallbladder cancer achieved a partial response (duration of 6.3 months), and 23 patients (26.4%) achieved stable disease (lasting &gt;6 months in one patient). OX40 receptor occupancy was maintained over 90% among all patients receiving doses of ≥200 mg, while no treatment-emergent antidrug antibodies were detected across all dose levels. Pharmacodynamic results demonstrated that treatment with INCAGN01949 did not enhance proliferation or activation of T cells in peripheral blood or reduce circulating Tregs, and analyses of tumor biopsies did not demonstrate any consistent increase in effector T-cell infiltration or function, or decrease in infiltrating Tregs. Conclusion No safety concerns were observed with INCAGN01949 monotherapy in patients with metastatic or advanced solid tumors. However, tumor responses and pharmacodynamic effects on T cells in peripheral blood and post-therapy tumor biopsies were limited. Studies evaluating INCAGN01949 in combination with other therapies are needed to further evaluate the potential of OX40 agonism as a therapeutic approach in patients with advanced solid tumors. Trial registration number NCT02923349 .
Deciphering the enigma of neuroendocrine prostate cancer
Authors: Fatima Karzai, Ravi A. Madan
Journal: Journal of Clinical Investigation (2022)

Despite the clinical advances in managing metastatic prostate cancer in the last 20 years, treatments for patients with metastatic disease only offer a brief respite from disease progression, especially after first-line therapies. Research into treatment resistance has defined a subset of patients with neuroendocrine differentiation of their prostate adenocarcinoma. Although neuroendocrine findings in conjunction with prostate adenocarcinoma can be seen in pathology samples at all stages of disease, the neuroendocrine variant of prostate cancer associated with poor outcomes occurs in approximately 20% of men with advanced disease. In this issue of JCI, Zhao, Sperger, and colleagues present data for a promising biomarker platform that can detect neuroendocrine prostate cancer after serial sampling of patients’ blood with a high degree of sensitivity and specificity. This assay will be tested in several current and future trials to better define its potential clinical role and perhaps provide a greater understanding of neuroendocrine prostate cancer itself.
Clonal lineage tracing reveals mechanisms skewing CD8+ T cell fate decisions in chronic infection
Authors: Moujtaba Y. Kasmani, Ryan Zander, H. Kay Chung, Yao Chen, Achia Khatun, Martina Damo, Paytsar Topchyan, Kaitlin E. Johnson, Darya Levashova, Robert Burns, Ulrike M. Lorenz, Vera L. Tarakanova, Nikhil S. Joshi, Susan M. Kaech, Weiguo Cui
Journal: The Journal of Experimental Medicine (2022)

Although recent evidence demonstrates heterogeneity among CD8+ T cells during chronic infection, developmental relationships and mechanisms underlying their fate decisions remain incompletely understood. Using single-cell RNA and TCR sequencing, we traced the clonal expansion and differentiation of CD8+ T cells during chronic LCMV infection. We identified immense clonal and phenotypic diversity, including a subset termed intermediate cells. Trajectory analyses and infection models showed intermediate cells arise from progenitor cells before bifurcating into terminal effector and exhausted subsets. Genetic ablation experiments identified that type I IFN drives exhaustion through an IRF7-dependent mechanism, possibly through an IFN-stimulated subset bridging progenitor and exhausted cells. Conversely, Zeb2 was critical for generating effector cells. Intriguingly, some T cell clones exhibited lineage bias. Mechanistically, we identified that TCR avidity correlates with an exhausted fate, whereas SHP-1 selectively restricts low-avidity effector cell accumulation. Thus, our work elucidates novel mechanisms underlying CD8+ T cell fate determination during persistent infection and suggests two potential pathways leading to exhaustion.
Positive patient-provider relationships among transgender and nonbinary individuals in New York City
Authors: Pablo K. Valente, Emily Allen Paine, William Mellman, Christine T. Rael, Caitlin MacCrate, Walter O. Bockting
Journal: International Journal of Transgender Health (2022)

Background: Transgender and nonbinary (TGNB) individuals have diverse health needs and may face disproportionate barriers to healthcare, including developing positive patient-provider relationships. While there is mounting evidence of gender-based stigma and discrimination in healthcare, little is known about how TGNB individuals develop positive patient-provider relationships.Aims: To examine TGNB individuals' interactions with healthcare providers and identify main characteristics of positive patient-providers relationships.Methods: We conducted semi-structured interviews with a purposive sample of 13 TGNB individuals in New York, NY. Interviews were transcribed verbatim and analyzed inductively for themes related to characteristics of positive and trusting relationships with healthcare providers.Results: Participants' mean age was 30 years (IQR = 13 years) and most participants were nonwhite (n = 12, 92%). Receiving peer referrals to specific clinics or providers helped many participants find providers perceived to be competent and created initial grounds for positive patient-provider relationships. Providers with whom participants had positive relationships commonly managed primary care and gender-affirming care and relied on a network of interdisciplinary providers for other specialized care. Providers who were positively evaluated were perceived to possess in-depth clinical knowledge on the issues they were responsible for managing, including gender-affirming interventions, particularly for TGNB patients who perceived themselves to be knowledgeable about TGNB-specific care. Provider and staff cultural competence and a TGNB-affirming clinic environment were also important, particularly early in the patient-provider relationship, and if combined with TGNB clinical competence.Discussion: Provider-focused training and education programs should combine components of TGNB clinical and cultural competence to facilitate development of positive relationships between TGNB patients and providers, thereby improving the health and wellbeing of TGNB people.
Advances in regenerative medicine applications of tetrahedral framework nucleic acid-based nanomaterials: an expert consensus recommendation
Authors: Yunfeng Lin, Qian Li, Lihua Wang, Quanyi Guo, Shuyun Liu, Shihui Zhu, Yu Sun, Yujiang Fan, Yong Sun, Haihang Li, Xudong Tian, Delun Luo, Sirong Shi
Journal: International Journal of Oral Science (2022)

Abstract With the emergence of DNA nanotechnology in the 1980s, self-assembled DNA nanostructures have attracted considerable attention worldwide due to their inherent biocompatibility, unsurpassed programmability, and versatile functions. Especially promising nanostructures are tetrahedral framework nucleic acids (tFNAs), first proposed by Turberfield with the use of a one-step annealing approach. Benefiting from their various merits, such as simple synthesis, high reproducibility, structural stability, cellular internalization, tissue permeability, and editable functionality, tFNAs have been widely applied in the biomedical field as three-dimensional DNA nanomaterials. Surprisingly, tFNAs exhibit positive effects on cellular biological behaviors and tissue regeneration, which may be used to treat inflammatory and degenerative diseases. According to their intended application and carrying capacity, tFNAs could carry functional nucleic acids or therapeutic molecules through extended sequences, sticky-end hybridization, intercalation, and encapsulation based on the Watson and Crick principle. Additionally, dynamic tFNAs also have potential applications in controlled and targeted therapies. This review summarized the latest progress in pure/modified/dynamic tFNAs and demonstrated their regenerative medicine applications. These applications include promoting the regeneration of the bone, cartilage, nerve, skin, vasculature, or muscle and treating diseases such as bone defects, neurological disorders, joint-related inflammatory diseases, periodontitis, and immune diseases.
Kidney tubular transcription co-activator, Yes-associated protein 1 (YAP), controls the expression of collecting duct aquaporins and water homeostasis
Authors: Yu Zhang, Huihui Huang, Yonglun Kong, Chunhua Xu, Liujiang Dai, Xiaoqiang Geng, Yujie Deng, Yang Wang, Yang Liu, Chenling Meng, Xiaoyi Zhang, Jinhong Li, Jinzhong Qin, Bo Feng, Kingston Kinglun Mak, Li Wang, Yu Huang, Weidong Wang, Hui-Yao Lan, Baoxue Yang, Hua A. Jenny Lu, Yin Xia
Journal: Kidney International (2022)

Final urine volume and concentration are defined by water reabsorption through the water channel proteins aquaporin (AQP)-2, -3 and -4 in the collecting duct. However, the transcriptional regulation of these AQPs is not well understood. The Hippo/Yes-associated protein 1 (YAP) pathway plays an important role in organ size control and tissue homeostasis. When the Hippo pathway including the Mst1/Mst2 kinases is inhibited, YAP is activated and functions as a transcription co-activator. Our previous work revealed a pathological role of tubular YAP activation in chronic kidney disease, but the physiological role of YAP in the kidney remains to be established. Here, we found that tubule-specific Yap knockout mice showed increased urine output and decreased urinary osmolality. Decreases in Aqp2, -3 and -4 mRNA and protein abundance in the kidney were evident in Yap knockout mice. Analysis of Mst1/Mst2 double knockout and Mst1/Mst2/Yap triple knockout mice showed that expression of Aqp2 and Aqp4 but not Aqp3 was dependent on YAP. Furthermore, YAP was recruited to the promoters of the Aqp2 and Aqp4 genes and stimulated their transcription. Interestingly, YAP was found to interact with transcription factors GATA2, GATA3 and NFATc1. These three factors promoted Aqp2 transcription in a YAP dependent manner in collecting duct cells. These three factors also promoted Aqp4 transcription whereas only GATA2 and GATA3 enhanced Aqp3 transcription. Thus, our results suggest that YAP promotes Aqp2 and Aqp4 transcription, interacts with GATA2, GATA3 and NFATc1 to control Aqp2 expression, while Aqp-2, -3 and -4 exploit overlapping mechanisms for their baseline transcriptional regulation.
Survival benefit of adequate lymphadenectomy in patients undergoing liver resection for clinically node-negative intrahepatic cholangiocarcinoma
Authors: Carlo Sposito, Francesca Ratti, Alessandro Cucchetti, Francesco Ardito, Andrea Ruzzenente, Stefano Di Sandro, Marianna Maspero, Giorgio Ercolani, Fabrizio Di Benedetto, Alfredo Guglielmi, Felice Giuliante, Luca Aldrighetti, Vincenzo Mazzaferro
Journal: Journal of Hepatology (2022)